tbuckley/cabot-search huggingface dataset:
Gemcitabine and rapamycin-loaded mixed polymeric thermogel for metastatic pancreatic cancer therapy
Authors: Seo Yeon Kim, Min Jeong Jo, Moon Sup Yoon, Chae Eun Jin, Yu Been Shin, Jae Min Lee, Hee Ji Shin, Joon Gyo Oh, Jae Min Cho, Hyunjun Kim, Hyunjin Park, Yong-Won Choi, Chun-Woong Park, Jin-Seok Kim, Dae Hwan Shin
Journal: Journal of Controlled Release (2023)

Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer-related death and has a poor 5-year overall survival. The superior therapeutic benefits of combination or co-administration of drugs as intraperitoneal chemotherapy have increased interest in developing strategies to deliver chemotherapeutic agents to patients safely. In this study, we prepared a gel comprising the thermosensitive poly(lactide-co-glycolide)-b-poly(ethylene glycol)-b-poly(lactide-co-glycolide) (PLGA-PEG-PLGA) polymer and gemcitabine (GEM), which is currently used as the primary chemotherapy for PDAC and rapamycin (RAPA), a mammalian TOR (mTOR) inhibitor, to deliver the drug through intraperitoneal injection. We performed in vitro cytotoxicity experiments to verify the synergistic effects of the two drugs at different molar ratios and characterized the physicochemical properties of the GEM, RAPA, and GEM/RAPA-loaded thermosensitive PLGA-PEG-PLGA gels, hereafter referred to as (g(G), g(R), and g(GR)), respectively. The g(GR) comprising PLGA-PEG-PLGA polymer (25% w/v) and GEM and RAPA at a molar ratio of 11:1 showed synergism and was optimized. An in vitro cytotoxicity assay was performed by treating Panc-1-luc2 tumor spheroids with g(G), g(R), or g(GR). The g(GR) treatment group showed a 2.75-fold higher inhibition rate than the non-treated (NT) and vehicle-treated groups. Furthermore, in vivo drug release assay in mice by intraperitoneal injection of g(G), g(R), or g(GR) showed a more rapid release rate of GEM than RAPA, similar to the in vitro release pattern. The drugs in the gel were released faster in vivo than in vitro and degraded in 48 h. In addition, g(GR) showed the highest anti-tumor efficacy with no toxicity to mice. These results provide evidence for the safety and efficacy of g(GR) for intraperitoneal drug delivery. This study will assist in developing and clinically administering topical anti-cancer formulations.
Longitudinal flux balance analyses of a patient with episodic colonic inflammation reveals microbiome metabolic dynamics
Authors: Arianna Basile, Almut Heinken, Johannes Hertel, Larry Smarr, Weizhong Li, Laura Treu, Giorgio Valle, Stefano Campanaro, Ines Thiele
Journal: Gut Microbes (2023)

We report the first use of constraint-based microbial community modeling on a single individual with episodic inflammation of the gastrointestinal tract, who has a well documented set of colonic inflammatory biomarkers, as well as metagenomically-sequenced fecal time series covering seven dates over 16 months. Between the first two time steps the individual was treated with both steroids and antibiotics. Our methodology enabled us to identify numerous time-correlated microbial species and metabolites. We found that the individual's dynamical microbial ecology in the disease state led to time-varying in silico overproduction, compared to healthy controls, of more than 24 biologically important metabolites, including methane, thiamine, formaldehyde, trimethylamine N-oxide, folic acid, serotonin, histamine, and tryptamine. The microbe-metabolite contribution analysis revealed that some Dialister species changed metabolic pathways according to the inflammation phases. At the first time point, characterized by the highest levels of serum (complex reactive protein) and fecal (calprotectin) inflammation biomarkers, they produced L-serine or formate. The production of the compounds, through a cascade effect, was mediated by the interaction with pathogenic Escherichia coli strains and Desulfovibrio piger. We integrated the microbial community metabolic models of each time point with a male whole-body, organ-resolved model of human metabolism to track the metabolic consequences of dysbiosis at different body sites. The presence of D. piger in the gut microbiome influenced the sulfur metabolism with a domino effect affecting the liver. These results revealed large longitudinal variations in an individual's gut microbiome ecology and metabolite production, potentially impacting other organs in the body. Future simulations with more time points from an individual could permit us to assess how external drivers, such as diet change or medical interventions, drive microbial community dynamics.
Targeting the Complement Pathway in Kidney Transplantation
Authors: Dela Golshayan, Nora Schwotzer, Fadi Fakhouri, Julien Zuber
Journal: Journal of the American Society of Nephrology (2023)

The complement system is paramount in the clearance of pathogens and cell debris, yet is increasingly recognized as a key component in several pathways leading to allograft injury. There is thus a growing interest in new biomarkers to assess complement activation and guide tailored therapies after kidney transplantation (KTx). C5 blockade has revolutionized post-transplant management of atypical hemolytic uremic syndrome, a paradigm of complement-driven disease. Similarly, new drugs targeting the complement amplification loop hold much promise in the treatment and prevention of recurrence of C3 glomerulopathy. Although unduly activation of the complement pathway has been described after brain death and ischemia reperfusion, any clinical attempts to mitigate the ensuing renal insults have so far provided mixed results. However, the intervention timing, strategy, and type of complement blocker need to be optimized in these settings. Furthermore, the fast-moving field of ex vivo organ perfusion technology opens new avenues to deliver complement-targeted drugs to kidney allografts with limited iatrogenic risks. Complement plays also a key role in the pathogenesis of donor-specific ABO- and HLA-targeted alloantibodies. However, C5 blockade failed overall to improve outcomes in highly sensitized patients and prevent the progression to chronic antibody-mediated rejection (ABMR). Similarly, well-conducted studies with C1 inhibitors in sensitized recipients yielded disappointing results so far, in part, because of subtherapeutic dosage used in clinical studies. The emergence of new complement blockers raises hope to significantly reduce the negative effect of ischemia reperfusion, ABMR, and nephropathy recurrence on outcomes after KTx.
Controlled spatial characteristics of ligands on nanoparticles: Determinant of cellular functions
Authors: Youngjin Choi, Bo Kyung Cho, Su Hyun Seok, Chansoo Kim, Ju Hee Ryu, Ick Chan Kwon
Journal: Journal of Controlled Release (2023)

Interactions of various ligands and receptors have been extensively investigated because they regulate a series of signal transduction leading to various functional cellular outcomes. The receptors on cell membrane recognize their specific ligands, resulting in specific binding between ligands and receptors. Accumulating evidence reveals that the receptors recognize the difference on the spatial characteristics of ligands as well as the types of ligands. Thus, control on spatial characteristics of multiple ligands presented on therapeutic nanoparticles is believed to impact the cellular functions. Specifically, the localized and multivalent distribution of ligands on nanoparticles can induce receptor oligomerization and receptor clustering, controlling intensity or direction of signal transduction cascades. Here, we will introduce recent studies on the use of material-based nanotechnology to control spatial characteristics of ligands and their effect on cellular functions. These therapeutic nanoparticles with controlled spatial characteristics of ligands may be a promising strategy for maximized therapeutic outcome.
Estrogen Therapy Induces Receptor-Dependent DNA Damage Enhanced by PARP Inhibition in ER+ Breast Cancer
Authors: Nicole A. Traphagen, Gary N. Schwartz, Steven Tau, Alyssa M. Roberts, Amanda Jiang, Sarah R. Hosford, Jonathan D. Marotti, Abigail E. Goen, Bianca A. Romo, Anneka L. Johnson, Emily-Claire K. Duffy, Eugene Demidenko, Paul Heverly, Yaron Mosesson, Shannon M. Soucy, Fred Kolling, Todd W. Miller
Journal: Clinical Cancer Research (2023)

Clinical evidence indicates that treatment with estrogens elicits anticancer effects in ∼30% of patients with advanced endocrine-resistant estrogen receptor α (ER)-positive breast cancer. Despite the proven efficacy of estrogen therapy, its mechanism of action is unclear and this treatment remains underused. Mechanistic understanding may offer strategies to enhance therapeutic efficacy.
Mutual ATRaction: Assessing Synergy of Berzosertib with Sacituzumab Govitecan
Authors: Stephanie A. Berg, Atish D. Choudhury
Journal: Clinical Cancer Research (2023)

A phase I trial of the novel combination of the ataxia telangiectasia and Rad3-related inhibitor berzosertib plus the antibody-drug conjugate sacituzumab govitecan in patients with heavily pretreatment tumors demonstrated some antitumor activity and no dose-limiting toxicities. This represents a new treatment paradigm that will be further explored in a phase II setting. See related article by Abel et al., p. 3603.
Sonoactivated Cascade Fenton Reaction Enhanced by Synergistic Modulation of Electron–Hole Separation for Improved Tumor Therapy
Authors: Su‐Ling Zhang, Cong Liu, Zhi‐Xiang Li, Ying‐Hua Guan, Lin Ge, Qijun Sun, Jun‐An Liu, Yong‐Jun Lin, Zi‐Xin Yang, Zeng‐Ying Qiao, Hao Wang
Journal: Advanced Healthcare Materials (2023)

Chemodynamic therapy (CDT) is an emerging targeted treatment technique for tumors via the generation of highly cytotoxic hydroxyl radical (·OH) governed by tumor microenvironment-assisted Fenton reaction. Despite high effectiveness, it faces limitations like low reaction efficiency and limited endogenous H2 O2 , compromising its therapeutic efficacy. This study reports a novel platform with enhanced CDT performance by in situ sono-activated cascade Fenton reaction. A piezoelectric g-C3 N4 (Au-Fe-g-C3 N4 ) nanosheet is developed via sono-activated synergistic effect/H2 O2 self-supply mediated cascade Fenton reaction, realizing in situ ultrasound activated cascade Fenton reaction kinetics by synergistic modulation of electron-hole separation. The nanosheets consist of piezoelectric g-C3 N4 nanosheet oxidizing H2 O to highly reactive H2 O2 from the valence band, Fe3+ /Fe2+ cycling activated by conduction band to generate ·OH, and Au nanoparticles that lower the bandgap and further adopt electrons to generate more 1 O2 , resulting in improved CDT and sonodynamic therapy (SDT). Moreover, the Au-Fe-g-C3 N4 nanosheet is further modified by the targeted peptide to obtain P-Au-Fe-g-C3 N4 , which inhibits tumor growth in vivo effectively by generating reactive oxygen species (ROS). These results demonstrated that the sono-activated modulation translates into a high-efficiency CDT with a synergistic effect using SDT for improved anti-tumor therapy.
Errors in Methods, Results, Table 1, and Supplement 1
Journal: JAMA Network Open (2023)

titled "Comparison of Work Patterns Between Physicians and AdvancedPractice Practitioners in Primary Care and Specialty Practice Settings," 1 published June 13, 2023, there were errors in several numbers in the Methods, Results, Table 1, and Supplement 1.The conclusions were not affected by these corrections.This article has been corrected.
Neoadjuvant Cabazitaxel plus Abiraterone/Leuprolide Acetate in Patients with High-Risk Prostate Cancer: ACDC-RP Phase II Trial
Authors: Neil E. Fleshner, Rashid K. Sayyid, Aaron R. Hansen, Joseph L.K. Chin, Ricardo Fernandes, Eric Winquist, Theodorus van der Kwast, Joan Sweet, Katherine Lajkosz, Miran Kenk, Karen Hersey, Rosette Veloso, Doron Berlin, Jaime O. Herrera-Caceres, Srikala Sridhar, Madeleine Moussa, Antonio Finelli, Robert J. Hamilton, Girish S. Kulkarni, Alexandre R. Zlotta, Anthony M. Joshua
Journal: Clinical Cancer Research (2023)

Early treatment intensification with neoadjuvant therapy may improve outcomes in patients with high-risk, localized prostate cancer treated with radical prostatectomy. Our objective was to compare pathologic, oncologic, and safety outcomes of neoadjuvant abiraterone acetate plus leuprolide acetate with or without cabazitaxel prior to radical prostatectomy in patients with localized, high-risk prostate cancer.This open-label, multicenter, phase II trial randomized men with clinically localized, D'Amico high-risk prostate cancer to neoadjuvant abiraterone acetate (1,000 mg/day) and leuprolide acetate (22.5 mg every 3 months) with or without cabazitaxel (25 mg/m2) prior to radical prostatectomy. The primary outcome was pathologic complete response (pCR) or minimal residual disease (MRD). Secondary outcomes included surgical margins, lymph node involvement, pathologic stage, 12-month biochemical relapse-free survival (BRFS) rates, and safety profile.The per-protocol population consisted of 70 patients [cabazitaxel arm (Arm A): 37, no cabazitaxel arm (Arm B): 33]. Median patient age and prostate-specific antigen levels were 63.5 years [interquartile range (IQR), 58.0-68.0] and 21.9 ng/mL (IQR, 14.6-42.8), respectively. pCR/MRD occurred in 16 (43.2%) versus 15 patients (45.5%) in arms A and B, respectively (P = 0.85). pCR occurred in two (5.4%) versus three patients (9.1%) in arms A and B, respectively (P = 0.66). Patients with ≤ 25% total biopsy cores positive had increased odds of pCR/MRD (P = 0.04). Patients with pCR/MRD had superior 12-month BRFS rates (96.0% vs. 62.0%, P = 0.03). Grade 3+ adverse events occurred in 42.5% and 23.7% of patients in arms A and B, respectively (P = 0.078).Neoadjuvant cabazitaxel addition to abiraterone acetate/leuprolide acetate prior to radical prostatectomy did not improve pCR/MRD in clinically localized, high-risk prostate cancer.
Efficacy of Metronomic Oral Vinorelbine, Cyclophosphamide, and Capecitabine vs Weekly Intravenous Paclitaxel in Patients With Estrogen Receptor–Positive, <i>ERBB2</i>-Negative Metastatic Breast Cancer
Authors: Elisabetta Munzone, Meredith M. Regan, Saverio Cinieri, Emilia Montagna, Laura Orlando, Ruichao Shi, Enrico Campadelli, Lorenzo Gianni, Michela Palleschi, Fausto Petrelli, Carmelo Bengala, Daniele Generali, Elena Collovà, Fabio Puglisi, Elisabetta Cretella, Claudio Zamagni, Claudio Chini, Barbara Ruepp, Sherene Loi, Marco Colleoni, Angelo Di Leo, Rolf A Stahel, Stefan Aebi, Paul Baas, Richard D Gelber, Keith McGregor, Solange Peters, Sanjay Popat, Rafael Rosell, Anita Hiltbrunner, Giuseppe Achille, Anne Carrer-Wagner, Daniela Celotto, Carmen Comune, Adriana Gasca, Nino Giacomelli, Roswitha Kammler, Rita Pfister, Heidi Roschitzki, Monica Ruggeri, Elizabeth Rugiati, Mirjam Schneider, Judith Schroeder, Sandra Troesch, Colleen Bouzan, Subrina Farah, Zhuoxin Sun, Holly Shaw, Lynette Blacher, Colleen King, Leslie Mundy, Dorene Polizzi, Monica Greco, Karolyn Scott, Robert Starkweather, Raffaella Ghisini, Roberto Masetti, Laura Amaducci, Ugo De Giorgi, Graziella Pinotti, Michela Donadio, Aron Goldhirsch
Journal: JAMA Oncology (2023)

In spite of the effectiveness of endocrine therapy plus cyclin-dependent kinase (CDK) 4/6 inhibitors as the first-line treatment for estrogen receptor (ER)-positive, erb-b2 receptor tyrosine kinase 2 (ERBB2 [formerly HER2/neu])-negative (ER+/ERBB2-) metastatic breast cancer (MBC), patients eventually develop resistance, and eventually most will receive chemotherapy. The METEORA-II trial compared a metronomic all-oral treatment with intravenous (IV) chemotherapy.
Early Detection of Lung Cancer Using Small RNAs
Authors: Tobias Sikosek, Rastislav Horos, Franziska Trudzinski, Julia Jehn, Maurice Frank, Timothy Rajakumar, Laura V. Klotz, Nathaniel Mercaldo, Mustafa Kahraman, Marco Heuvelman, Yasser Taha, Jennifer Gerwing, Jasmin Skottke, Alberto Daniel-Moreno, Marta Sanchez-Delgado, Sophie Bender, Christina Rudolf, Franziska Hinkfoth, Kaja Tikk, Judith Schenz, Markus A. Weigand, Peter Feindt, Christian Schumann, Petros Christopoulos, Hauke Winter, Michael Kreuter, Marc A. Schneider, Thomas Muley, Stephan Walterspacher, Martin Schuler, Kaid Darwiche, Christian Taube, Balazs Hegedus, Klaus F. Rabe, Kimberly Rieger-Christ, Francine L. Jacobsen, Clemens Aigner, Martin Reck, Alexander A. Bankier, Amita Sharma, Bruno R. Steinkraus
Journal: Journal of Thoracic Oncology (2023)
BCR/Integrin Interaction in CLL: A Physiologic Remnant with Clinical Relevance
Authors: Erika Tissino, Riccardo Bomben, Valter Gattei, Antonella Zucchetto
Journal: Clinical Cancer Research (2023)

Summary CD49d, the alpha chain of the very late antigen-4 (VLA-4) integrin, has a negative prognostic impact in chronic lymphocytic leukemia treated with the Bruton's tyrosine kinase (BTK) inhibitors, ibrutinib and acalabrutinib. Despite BTK inhibition, VLA-4 remains inside-out activated via B-cell receptor, an activation dampened by phosphoinositide 3-kinase inhibitors. Evaluation of CD49d expression in patients starting BTK inhibitor therapy may improve their prognostic stratification. See related article by Alsadhan et al., p. 3612
A key role for platelet GPVI in neutrophil recruitment, migration, and NETosis in the early stages of acute lung injury
Authors: Philipp Burkard, Charlotte Schonhart, Timo Vögtle, David Köhler, Linyan Tang, Denise Johnson, Katherina Hemmen, Katrin G. Heinze, Alexander Zarbock, Heike M. Hermanns, Peter Rosenberger, Bernhard Nieswandt
Journal: Blood (2023)

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are associated with high morbidity and mortality. Excessive neutrophil infiltration into the pulmonary airspace is the main cause for the acute inflammation and lung injury. Platelets have been implicated in the pathogenesis of ALI/ARDS, but the underlying mechanisms are not fully understood. Here, we show that the immunoreceptor tyrosine-based activation motif-coupled immunoglobulin-like platelet receptor, glycoprotein VI (GPVI), plays a key role in the early phase of pulmonary thrombo-inflammation in a model of lipopolysaccharide (LPS)-induced ALI in mice. In wild-type (WT) control mice, intranasal LPS application triggered severe pulmonary and blood neutrophilia, hypothermia, and increased blood lactate levels. In contrast, GPVI-deficient mice as well as anti-GPVI-treated WT mice were markedly protected from pulmonary and systemic compromises and showed no increased pulmonary bleeding. High-resolution multicolor microscopy of lung sections and intravital confocal microcopy of the ventilated lung revealed that anti-GPVI treatment resulted in less stable platelet interactions with neutrophils and overall reduced platelet-neutrophil complex (PNC) formation. Anti-GPVI treatment also reduced neutrophil crawling and adhesion on endothelial cells, resulting in reduced neutrophil transmigration and alveolar infiltrates. Remarkably, neutrophil activation was also diminished in anti-GPVI-treated animals, associated with strongly reduced formation of PNC clusters and neutrophil extracellular traps (NETs) compared with that in control mice. These results establish GPVI as a key mediator of neutrophil recruitment, PNC formation, and NET formation (ie, NETosis) in experimental ALI. Thus, GPVI inhibition might be a promising strategy to reduce the acute pulmonary inflammation that causes ALI/ARDS.
Venetoclax abrogates the prognostic impact of splicing factor gene mutations in newly diagnosed acute myeloid leukemia
Authors: Jayastu Senapati, Samuel Urrutia, Sanam Loghavi, Nicholas J. Short, Ghayas C. Issa, Abhishek Maiti, Hussein A. Abbas, Naval G. Daver, Naveen Pemmaraju, Sherry Pierce, Kelly S. Chien, Koji Sasaki, Tapan M. Kadia, Danielle E. Hammond, Gautam Borthakur, Keyur Patel, Farhad Ravandi, Hagop M. Kantarjian, Guillermo Garcia-Manero, Courtney D. DiNardo
Journal: Blood (2023)
A commitment to act on data sharing
Authors: Kamran Abbasi
Journal: BMJ (2023)

The argument is simple enough.Ensuring that research is registered in advance, the findings reported quickly, and the data and code shared readily is in the best interests of science and the public good.Ultimately, the public pays for the research enterprise, and the scientific community must be held accountable.But nothing that involves commercial interests, academic rivalry, political agendas, and the perverse incentives of scientific publishing is ever simple.What is simple and obvious, such as the importance of sharing data and code from research, rapidly becomes complex and insoluble (
Likelihood-Based Tests of Species Tree Hypotheses
Authors: Richard Adams, Michael DeGiorgio
Journal: Molecular Biology and Evolution (2023)

Likelihood-based tests of phylogenetic trees are a foundation of modern systematics. Over the past decade, an enormous wealth and diversity of model-based approaches have been developed for phylogenetic inference of both gene trees and species trees. However, while many techniques exist for conducting formal likelihood-based tests of gene trees, such frameworks are comparatively underdeveloped and underutilized for testing species tree hypotheses. To date, widely used tests of tree topology are designed to assess the fit of classical models of molecular sequence data and individual gene trees and thus are not readily applicable to the problem of species tree inference. To address this issue, we derive several analogous likelihood-based approaches for testing topologies using modern species tree models and heuristic algorithms that use gene tree topologies as input for maximum likelihood estimation under the multispecies coalescent. For the purpose of comparing support for species trees, these tests leverage the statistical procedures of their original gene tree-based counterparts that have an extended history for testing phylogenetic hypotheses at a single locus. We discuss and demonstrate a number of applications, limitations, and important considerations of these tests using simulated and empirical phylogenomic data sets that include both bifurcating topologies and reticulate network models of species relationships. Finally, we introduce the open-source R package SpeciesTopoTestR (SpeciesTopology Tests in R) that includes a suite of functions for conducting formal likelihood-based tests of species topologies given a set of input gene tree topologies.
A nerve-preserving strategy for endoscopic submucosal dissection of superficial pharyngeal cancers
Authors: Takehide Fukuchi, Kingo Hirasawa, Ryosuke Ikeda, Masafumi Nishio, Ryosuke Kobayashi, Chiko Sato, Shin Maeda
Journal: Endoscopy (2023)

Endoscopic submucosal dissection (ESD) as a treatment for superficial pharyngeal cancer has been developed and widely accepted by endoscopists in Japan [1] [2]. However, a lack of anatomical knowledge can cause complications that are not experienced with gastrointestinal ESD. In the subepithelial layer of the pharyngeal region, the superior laryngeal nerve is a branch of the vagus nerve. The nerve consists of two branches, one of which is the internal laryngeal nerve that supplies sensory fibers to the laryngeal mucosa [3]. Damage to this nerve may result in postoperative dysphagia and hoarseness due to laryngeal hyposensitivity [4] [5]. As we have encountered several similar complicated cases, we have developed a strategy for preserving the internal laryngeal nerve during pharyngeal ESD. Here, we present a successful case of nerve preservation ([Video 1]).